Asymmetric quaternary ester-salts of morpholine



Patented July 10, 19 45 ASYMMETRIC QUATERNARY ESTER-SALTS OF MORPHOLINEJoseph B. Niederl, Victor Niederl, and Martin McGreal, Brooklyn, N. Y.

No Drawing.

This invention relates to asymmetric quaternary ester-salts ofmorpholine and to the process by which they are produced.

In our previous applications, Serial Nos. 393,672, filed May 15, 1941;$38,896, filed April 14, 1942; and 471,024, flied January 1, 1943, thereare disclosed various quaternary ammonium salts of morpholine includingtheir ester-salts. vIn the preparation and evaluation of thesecompounds, it was discovered that, in order to obtain the best balanceof chemical, physical, and physiological properties in such'quatemaryammonium estersalts, it is often necessary to produce wholly asymmetriccompounds by having each of the three available valences of morpholinesatisfied with different substituent groups. N-myristyl-N-benzylmorpholinium ethosulfate aflords an excellent illustration of theadvisability of having each of the substituents on the morpholiniumnitrogen atom different. This compound is a crystalline substance of lowtoxicity and high germicidal properties, having a phenol coeflicient ofv500; is

completely water soluble and is exceedingly stable even in highlyalkaline solutions. It is produced by first forming aN-myristyl-N-benzyl morpholinium halide and then further reacting thisintermediate product with a mono-metal salt .of monoethyl sulfate, suchas silver, potassium or sodium ethyl sulfate. If this process is alteredby reacting N-myristyl morpholine in a single step with a simpleester-sulfate, such as diethyl sulfate, to produce N-myristyl-N-ethylmorpholinium ethosulfate, a hygroscopic syrup is obtained which can becrystallized only with the greatest of dimculty. Likewise, if the halideis not removed to form an ester-salt, the intermediate compound is muchless soluble in water than the ester-salt and decomposes in weaklyalkaline solutions. Furthermore, if the myristyl group is replacedwithother' alkyl groups, such as a cetyl group, without replacing theother groups, certain bactericidal properties areadversely effected.Thus, in N-myristyl-N benzyl. morpholinium ethosulfate, the benzyl groupapparently imparts crystalline properties, the ethosulfate' groupexceptional stability and solubility, and the myristyl Collec-'Application September 9, 1944, Serial No. 553,466

13 Claims. 01. 260-247) groupon the morpholine nitrogen atom isdifferent thereby -making it possible to procure an intramolecularsynchronization not possible when two or more of the substituent groupsare the same.

It is a special object to provide new and improved bactericidal agents.

- Other objects, features and purposes of the invention will be obviousfrom the following more detailed description.-

f The compounds of this invention may be represented by the formulaCHi-CH: R I 0 N AcY- CHr-QHI wherein R is an alkyl radical of at least12 carbon atoms, R and Y are hydrocarbon radicals of less than 12 carbonatoms differing from one another, and AC is an acid radical. In aspecial embodiment AC is a $04 radical but may be any polyvalent acidradical. R. may be a lauryl 'myristyl, cetyl, octadecyl or other alkylradicals of more than 12 carbon atoms. B" may be a benzyl, phenylethylcinnamyl or similar aralkylradical, a methyl, ethyl propyl or like alkylradical, or a cycloalkyl radical such as a cyclohexyl or similar alkyl,aralkyl or cycloalkyl radical of less than 12 carbon atoms. Y islikewise analkyl, cycloalkyl or an aralkyl radical of less than 12carbon atoms but is different from R. In a special embodiment Y is a lowmolecular alkyl radical of not more than 8 carbon atoms.

The asymmetric quaternary ammonium esters'alts of this invention aredistinguished from the simple ester-salts of morpholine not only intheir properties but also in the method by which they are produced. Thesimple ester-salts of morpholine wherein Y, in the anionic part of themolecule,

is identical with one or more or all of the substituent radicals in thecationic part of the molecule are generally produced in a single step byreacting a tertiary morpholine with a di-ester of a polybasic acid suchas, sulfuric acid. For example, a N-myristyl-N-ethyl morpholiniumethosulfate can be produced by reacting N-myristyl morpholine withdiethyl sulfate. However, N-

quaternary ammonium morpholinium halide and the sulfates then reactingthis compound with a mono-salt of esters of di-or other polybasic acids,such as, sodium, potassium and-silver salts of esters of sulfuric,malonic, succinic, phthalic, carbonic, phosphoric and similar acids.Typical compounds produced according to this procedure are thephosphates havingthe formula PO|YI cnr-o, n'

having the formula OKs-CH: R-

O/ BOIY" cnr-c. \R' the carbonates having the formula orb-H, a-

O COaY- CH:C R'- and the like, wherein the substituent groups have thesignificance hereinbefore stated.

ExAMPLn I One-tenth mol of potassium ethyl sulfate which has beendissolved in 100 ml. of hot ethyl alcohol is added to 0.1 mol ofN-benzyl-N-myristyl morpholinium chloride, prepared as described in U.S.

patent application Serial No. 471,024, dissolved in 50 ml. of ethylalcohol. The reactants are refluxed for 4 hours, and after cooling thereaction mixture to room temperature, it is filtered and then evaporatedto dryness. The dry residue is dissolved in hot ethyl acetate, filteredto remove any remaining inorganic matter, and allowed to crystallize.The crystalline N-benzyl-N-myristyl morpholinium ethosulfate thusobtained is recrystallized from ethyl acetate and then has a.

Alternative procedure '(a) One-tenth mol of N-benzyl-N-myristylmorpholinium bromide, prepared as described in U. S. patent applicationSerial No. 471,024, is dissolved in ml. of ethyl alcohol and to thissolution is added 0.1 mol of potassium ethyl sulfate dissolved in 100ml. of distilled water. This re-' action mixture is refluxed for 8 hoursand then evaporated to dryness on a steam bath. The dry and solidmaterial is triturated with 100 ml. of

cold ethyl alcohol, filtered and again evaporated to dryness. Then theproduct is dissolved in hot ethyl acetate, filtered to remove the lasttraces of inorganic material, and allowed to crystallize. Thecrystalline N-benzyl-N-myrlstyl morpholinium ethosulfate is once morerecrystallized from ethyl acetate and then melts at 94 to 96 C.

ExsurnsII One-tenth mol of potassium ethyl sulfate which has beendissolved in 100 ml. of hot ethyl alcohol is added to 0.1 mol ofN-benzyl-N-lauryl morpholinium chloride, prepared as described in U. B.

. patent application Serial No. 471,024, dissolved in 50 ml. of ethylalcohol. The reactants are refluxed for 4 hours, and after cooling thereaction mixture to room temperature it is filtered and then evaporatedto dryness. The dry residue is dissolved in hot ethyl acetate, filteredto remove any remaining inorganic matter and'allowed to crystallize. Thecrystalline N-benzyl- N-lauryl morpholinium ethosulfate thus obtained isrecrystallized trom ethyl acetate and thus has a melting point of 89 to90 C. The product is soluble in water, ethyl and methyl alcohol and hotethyl acetate. It is slightly soluble in benzene and toluene andpetroleum ether, and insoluble in ether.

EXAMPLE III One-tenth mol of potassium ethyl sulfate dissolved in ml. ofhot ethyl alcohol is added 0 to 0.1 mol of N-benzyl-N-cetyl morpholiniumbromide, prepared as described in U. S. patent application Serial No.471,024, dissolved in 50 ml. of ethyl alcohol. This reaction mixture isrefluxed for 4 hours, allowed to cool and then filtered. The filteredalcoholic solution is evaporated to dryness; the residue is dissolved inhot ethyl acetate and again filtered to remove the last traces ofinorganic matter, and allowed to crystallize. The crystallineN-benzyl-N-cetyl morpholinium ethosulfate is again recrystallized fromethyl acetate, and thus purified, has a melting point of to 116 C. Thecompound is soluble in water, and very soluble in ethyl and methylalcohol and hot ethyl acetate; it is very slightly soluble in benzenetoluene and petroleum ether, and insoluble in ether. e

In the same manner, N-benzyl-N-octadecyl morpholinium ethosulfate whichis crystalline and melts at 120 to C. may-be prepared. It is 40 fairlysoluble incold water, soluble in all proportions in hot water, verysoluble 'in ethyl and methyl alcohol and hot ethyl acetate; it is veryslightly soluble in petroleum ether benzene, and toluene, and insolublein ether. 1

EXAMPLE IV One-tenth mol of N-benzyl-N-cetyl morpholinium chloride,prepared as described-in U. S. patent application Serial No. 471,024,Example I,

50 is dissolved in 250 ml. of ethyl alcohol. Onetenth mol of potassiummethyl sulfate'is added, and the reaction mixture is refluxed for 16hours. The solution is permitted to cool, is filtered to remove theorganic material, and then evaporated to dryness. The residual dry massis dissolved in hot ethyl acetate, again filtered to remove the lasttraces of inorganic matter, and'left standing to allow the product tocrystallize. The crystalline material thus obtained is N-benzyl-N-cetylmorpholinium 'methosulfate, and is recrystallized from ethyl acetate. Ithas a melting point of 101 to 103 C. This compound is fairly soluble incold, water, completely soluble in hot water, and

very soluble in ethyl and methyl alcohol and hot ethyl acetate; it issparingly soluble in petroleum ether, practically insoluble in benzeneand toluene and insoluble in ether.

By following the above procedure and using other N-benzyl-N-alkylmorpholinium chlorides or bromides, such as, N-benzyl-N-laurylmorpholinium chloride or bromide, N-benzyl-N- myristyl morpholiniumchloride or bromide, N-

benzyl-N-octadecyl morpholinlum chloride or bromide. (Prepared asdescribed m U. B. patent application Serial No. 471,024.) The respectivemides, N-ethyl-N-lauryl morpholinium arates out on cooling. meltingpoint of 110 to ll6 C. It is soluble in morpholinium iodide,

' going ave examples, any

N-benzyl-N-allryl morpholinium methosuliates, such as, N-benzyl-N-laurylmorpholinium methosulfate, which has a melting point of 85 to 87 C.,

N -benzyl-N-myristyl morpholinium methosulfate, which has a meltingpoint of 90 to 92 C., N-benzyl-N-octadecyl morpholinium methosulfate,which has 'a melting point of 112 to 113 C., are obtained.

Similarly, N-ethyl-N-alkyl morpholinium brobromide, N-ethyl-N-myristylmorpholinium bromide, N- ethyl-N-cetyl morpholinium bromide, and N-ethyl-N-octadecyl morpholinium bromide. prepared as described in U. S.patent application Serial No. 393,672, and in Journal American ChemicalSociety, vol. 63, page 1476, are converted into the respectiveethosulfates by following Examples l to 4, and into the respectivemethosulfates by following Example 5.

EXAMPLE V One-tenth of a mol of N-methyl-N-cetyl morpholinium iodide,prepared as described in U. S. patent application Serial No. 435,638,Example I, is completely dissolved in hot ethylalcohol. To

this solution, contained in a suitable reilux ap-' is added, in smallportions, 100 ml. of a hot ethyl alcohol solution containing 0.1 mol ofpotassium ethyl sulfate. The mixture is refluxed several hours and thenthe alcohol is distilled off. The residue is and filtered. The finalreaction product, the N- methyl-N-cetyl morpholinium ethosulfate, sep-This compound has a paratus,

water, very soluble inethyl and methyl alcohol, and hot ethyl acetate;it is very slightly soluble in benzene, toluene, and petroleum ether,and in. soluble in ether.

In a similar manner the N-methyl-N-lauryl morpholinium iodide,N-methyl-N-myristyl morpholinium iodide, and N-methyl-N-octadecylprepared as described in U. S. patent application Serial No. 435,638,are converted into the respective ethosulfates.

By following the above procedures and examples, asymmetric piperidiniumester-salts are pretriturated with hot ethyl acetate ample, by treatingany of the high molecular quarternary ammonium halides, such as the N-lauryl-N-myristyl-N-cetyl or N-octadecyl-N-aryl- N,N-di-alkyl ammoniumhalides with sodium, potassium or silvermethylor ethyl sulfate, therespective methoor ethosulfates are obtained possessing partiallyenhanced or physiological properties. p

In instances where it is merely desirable to solubilize the halides,it-is not necessary to actually isolate the final reaction product norto use equimolar quantities of the alkali salts of the sulfuric acidmono-esters. Thus, solutions of the halide may be refluxed with suchsubmolar quantitles of sulfate as to produce concentrated homogeneousaqueous solutions of mixtures of halide and sulfate, for use incommercial antiinvention.

We claim: 1. A process for producing asymmetric estersalts'of morpholinewhich comprises reacting a quaternary ammonium morpholinium halide witha mono-metal salt of an ester of a polybasic acid. 2. A process forproducing a capillary-active water-soluble and bactericidal compositionwhich comprises reacting a quaternary ammoniumv halide of morpholinecontaining analkyl radical of at least 12 carbon atoms substituted-onthe nitrogen atom with a mono-metal salt or an alkyl ester of sulfuricacid.

3. A process for producing asymmetric quaterester-salts ofmorpholine'which nary ammonium morpholine substituted on its comprisesreacting nitrogen atom with a high molecular hydrocarbon pared just aseasily and efllciently. Thus N- lauryl-N-myristyl-N-cetyl, or theN-octadecyl-N- benzyl-piperidinium halides can be converted into therespective N-lauryl-N-myristyl-N-cetyl or N-octadecyl-N-benzyl-piperidinium methoorethosulfates with synchronizedintramolecular characteristics and properties.

In a similar manner, we obtain asymmetric quaternary ammoniumester-salts of such N- deterocyclics in which three valences of thenitrogen atom are already utilized within the ring, as

in pyridine, quinoline, iso-quinoline, nicotine and the like. Thus, forexamples, by utilizing any of the above procedures theN-lauryl-N-myristyl- N-cetyl or N-octadeeyl pyridinium, quinolinium,iso-quinolinium or nicotinium halides may be converted into therespective methoor ethosulfates.

Furthermore, the present invention is not limited to the production orwholly asymmetric quaternary ammonium ester-salts only, but canbe-advantageously used to produce mixed, but not wholly asymmetricalquaternary ammonium ester-salts, to aflect partial intramolecularsynchronization of desirableproperties. Thu by again followingprocedures selected from the forequaternary ammonium halide may beconverted into the respective quaternary ammonium ester-salts. For ex.-

group with an aralkyl halide to form a quaternary ammonium halide ofmorpholine substituted on its nitrogen atom by said alkyl andaralkylradicals, and then reacting said halide with a monometal saltofan alkyl ester of a polybasic acid to form an asymmetrical quaternaryammonium ester-salt of morpholine.

4. A process for producing N-benzyl-N-myrlstyl morpholinium ethosulfatewhich comprises reacting an N-benzyl-N-myristyl morpholinium halide withpotassium ethyl sulfate;

5. .A process for producing water-soluble and capillary-activebactericidal compositions which I comprises reacting a quaternaryammoniummorpholinium halide substituted by an alkyl radical of at least12 carbon atoms and a hydrocarbon radical of less than 12 carbon atomswith a monometal salt of ethyl sulfate to form an asymmetric ester-saltor morpholine.

6. A process for producinga water-soluble and capillary-activebactericidal composition, which comprises reacting a. quaternaryammonium halide of morpholine substituted on its nitrogen atom only byhydrocarbon radicals-of which one is an alkyl radical of at least 12carbon atoms and the other is a. hydrocarbon radical of less than 12carbon atoms, with a mono-metal salt of an alkyl' ester of a polybasicacid. the ester forming radical containing less than12 carbon atoms andbeing diflerent from any of the substituents on the nitrogen atom.

'7. A process for producing esterphysical, chemical,

salts of morpholine which comprises reacting a hydrocarbon substitutedmorpholine with a halogen substituted hydrocarbon to form a hydrocarbonsubstituted quaternary morpholinium halide and reacting thisintermediate product with a mono-metal salt of a poiybasic acid ester toform the asymmetric ester-salts.

8. Water-soluble capillary-active compounds having the general formulacmpm 3+ 0 N sorr- V in which R'is an alkyl radical of at least 12 carbonatoms, R is a hydrocarbon radical of less than 12 carbon atoms, and Y isan alkyl radical of loss than 12 carbon atoms differing from R.

9. A water-soluble capillary-active bactericidal compound, anNalkyl-N-benzyl morpholinium allwl sulfate, wherein the alkyl radicalsubstituted on the nitrogen atomcontains 12 to 18 carbon CBS-C I 3'atoms and the alkyl radical substituted on the compound,N-benzyl-N-myristyl morpholinium' ethoslflfate.

12. A water-soluble capillary-active bactericidal compound,N-benzyl-N-myristyl morpholinium methosuliate.

' 13. A water-soluble capillary-active bactericidal compound,N-benzyl-N-myristyi morpholinium ethosuliate.

JOSEPH B. NIEDERL. VICTOR NIEDERL. MARTIN McGREAL.

